It is now commonly accepted among scientists that the primary causes of lipoatrophy are the drugs Zerit (stavudine) and Retrovir (zidovudine). Studies show that Zerit is somewhat worse than Retrovir in this regard. The prevailing theory for how the drugs eliminate fat has to do with the energy producing centers of all cells, called the mitochondria. Specifically, Zerit and Retrovir can significantly damage the mitochondria in fat cells. Whether the cells simply cease to function properly, or actually die, hasn't been proven conclusively. Many experts, however, believe that both occur. Some studies have found hints that protease inhibitors, or the non-nucleoside reverse transcriptase inhibitor (NNRTI) called efavirenz (found in Sustiva and Atripla), may also contribute to lipoatrophy. These results have not been consistent, however. It's likely that HIV itself may also damage cellular mitochondria, but it seems to be Zerit and Retrovir that tip the balance.

With lipohypertrophy, however, it's a lot less clear what the causes may be. Here is a review of what we do and don't know about the possible causes of lipohypertrophy:

Protease inhibitors (PIs): Some researchers believe that protease inhibitors can impair the ability of certain enzymes responsible for mopping up excess fat and keeping fat cells functional. This, in turn, would account for the high levels of lipids being seen in some people living with HIV. This might also explain why fat accumulates around the gut, breasts, or neck. It's still not clear which protease inhibitors are most likely to cause lipodystrophy. Two protease inhibitors, Reyataz (atazanavir) and Prezista (darunavir), are less likely to cause increased lipid levels in the blood (the risk of raised lipid levels may increase slightly when Reyataz or Prezista is combined with low-dose Norvir). Neither drug has been associated with fat accumulation in any studies.

In HIV-negative people, lipohypertrophy frequently goes hand-in-hand with elevated cholesterol and triglycerides, and detrimental changes in the body's production of insulin, which regulates blood sugar. When such people are able to lose accumulated fat, particularly in the gut, their lipid and insulin problems often improve. This would indicate that the fat accumulation causes the troubled blood chemistry, but some studies suggest that lipid and insulin problems can increase the chance that a person will accumulate gut fat. If the latter is true, this may help explain why some have found a link between protease inhibitor use and fat accumulation—PIs often increase lipids, and might also decrease insulin sensitivity

Nucleoside reverse transcriptase inhibitors (NRTIs): The same two NRTIs that have been tied to lipoatrophy—Zerit and Retrovir—have also been linked with reduced insulin sensitivity and diabetes. As we explained above, trouble processing blood sugar is frequently associated with increased body fat accumulation

Other factors: Not everyone taking PIs or NRTIs develops lipodystrophy or problems with fat or sugar levels in the blood. In turn, researchers have been looking into other factors that may increase the risk of lipohypertrophy and lipoatrophy while on ARV treatment. For example, people who start HIV treatment with lower CD4 cell counts may be at a higher risk of developing lipodystrophy than those who start treatment with higher CD4 cell counts. People who are older when they start treatment may also be at a higher risk, compared to those who are younger when treatment is started. And the longer a person has been on an HIV drug regimen that contains certain PIs and/or NRTIs, the greater the risk of lipodystrophy or fat/sugar-related problems.

HIV itself may be a factor to consider. Long before people started taking HIV drug combinations, people living with HIV were more likely to have higher levels of triglycerides in their blood and to experience body-shape changes, compared to HIV-negative people. And because many HIV-positive people are living longer while on combination HIV drug therapy, the HIV-related fat problems continue to get worse. Researchers are still looking into the effects of HIV (and problems with the immune system) on the way our bodies store and utilize lipids. They are also looking at how uncontrolled HIV affects more than just the immune system. Greater HIV replication has been tied to a greater risk for heart attacks, thickening of the arteries, and possibly insulin resistance—all of which are tied to gut fat accumulation in people not infected.

People with HIV are also far more likely than the general population to be smokers or former smokers. Numerous studies in HIV-negative people have found that cigarette smoking not only leads to the development of plaque in the arteries, it also is commonly associated with high cholesterol and triglycerides, problems with insulin and with gut fat accumulation—especially in men.

Researchers have also been looking into genetic factors that may increase or decrease the risk of lipodystrophy and problems with fat or sugar levels in the blood. Some people may have genetic mutations—scientifically known as "polymorphisms"—that may affect the way cells in the body (including fat cells) work. People with these polymorphisms taking certain HIV medications may be at an increased risk for body-shape changes and problems with fat or sugar levels in the blood. More research is needed to better understand our genetic differences and the role they may play in the side effects of HIV drug treatment.

Last Revised: June 21, 2011

This content is written by the POZ and AIDSmeds editorial team. For more information, please visit our "About Us" page.